Studies carried out by our laboratory during the current funding cycle, reached important milestones in the characterization of b1 integrins as novel regulators of intracellular signaling pathways participating in tumor progression in vivo. Using molecular and genetically engineered models of prostate cancer, we have now established a central role for b1 integrins in orchestrating cross-talk signaling with growth factor receptors, mostly the insulin-like growth factor receptor-1 (IGF-IR), modulating the activation of cytoplasmic kinases, including AKT and Focal Adhesion Kinase (FAK), and promoting tumor cell survival by counteracting apoptosis. We found that these responses are prominently exploited in prostate cancer progression, where b1 integrin-directed signaling is required for primary tumor growth, promotes metastatic dissemination, and antagonizes tumor response to therapy, especially ionizing radiation. Therefore, we formulated a unifying hypothesis that b1 integrins orchestrate multiple intracellular signaling pathways of gene expression, cell motility and cell survival in prostate cancer progression and this will constitute the focus of the present application for the next funding cycle. Experiments in specific aim 1 will dissect the role of b1 integrins in vitro and in vivo in the control of the sonic hedgehog pathway in tumor cells. The pro-metastatic functions of b1 integrins through a novel pathway of tumor cell migration and metastasis will be investigated in the second specific aim, with emphasis on dynamic redistribution of b1 integrins by Trop-2, a transmembrane receptor that is up-regulated in prostate cancer, in specialized subcellular microdomains of prostate cancer cells. The third specific aim will characterize a novel cell survival mechanism mediated by b1 integrins in prostate cancer cells, and centered on their selective inhibition of JNK1-mediated apoptosis in response to ionizing radiation. Overall, the application combines detailed elucidation of mechanistic pathways in vitro, with validation studies using state-of-the-art molecular and genetic models of prostate cancer in vivo. The results will uncover novel aspects of b1 integrin signaling important for cancer progression, and will establish a mechanistic foundation for novel translational approaches in prostate cancer therapy. PUBLIC HEALTH RELEVANCE: The present study will elucidate a novel molecular network of synergistic cooperation between surface receptors and their downstream targets, and it will provide new insights in the current therapeutic approaches for prostate cancer that target either integrins or the insulin-like growth factor receptor. This line of investigations will establish a broad mechanistic foundation for novel translational approaches in the treatment of advanced and metastatic prostate cancer. Overall, the application combines multidisciplinary state-of-the-art approaches from several fields of investigation into a single, integrated experimental platform, uniquely positioned to unravel novel pathogenetic mechanisms of prostate cancer progression.